Fetal alcohol syndrome: an examination of craniofacial dysmorphology in Macaca nemestrina

The purpose of this investigation was to evaluate the craniofacial features in nonhuman primate models exposed in utero to moderate and high weekly binge doses of ethanol. While the high-dosed animal did have unusual craniofacial dysmorphology, she did not exhibit the typical facial pattern seen in human fetal alcohol syndrome. The high-dosed specimen displayed a scaphocephalic head shape secondary to synostosis of the sagittal suture. The brain of this monkey was grossly abnormal and microcephalic.     

Craniofacial sutures: Signaling centres integrating mechanosensation,cell signaling,and cell differentiation

Cranial sutures are dynamic structures in which stem cell biology, bone formation, and mechanical forces interface, influencing the shape of the skull throughout development and beyond. Over the past decade, there has been significant progress in understanding mesenchymal stromal cell (MSC) differentiation in the context of suture development and genetic control of suture pathologies, such as craniosynostosis. More recently, the mechanosensory function of sutures and the influence of mechanical signals on craniofacial development have come to the forefront. There is currently a gap in understanding of how mechanical signals integrate with MSC differentiation and ossification to ensure appropriate bone development and mediate postnatal growth surrounding sutures. In this review, we discuss the role of mechanosensation in the context of cranial sutures, and how mechanical stimuli are converted to biochemical signals influencing bone growth, suture patency, and fusion through mediation of cell differentiation. We integrate key knowledge from other paradigms where mechanosensation forms a critical component, such as bone remodeling and orthodontic tooth movement. The current state of the field regarding genetic, cellular, and physiological mechanisms of mechanotransduction will be contextualized within suture biology.     

Methylenetetrahydrofolate reductase C677T variant in Indian children with craniosynostosis: Its role in the pathogenesis,risk of craniosynostosis

BACKGROUND:

677C to T allele in the 5, 10-methylenetetrahydrofolate reductase (MTHFR) gene has been implicated in the etiology of various syndromes and nonsyndromic diseases but till date no direct studies have been reported with craniosynostosis.

OBJECTIVES:

The aim was to study the family-based association of MTHFR polymorphism in different categories of craniosynostosis patients.

MATERIALS AND METHODS:

This was a cross-sectional study in which 30 patients classified as Apert syndrome, Pfeiffr syndrome and nonsyndromic craniosynostosis patients with their family were recruited. A sample of 3 ml intravenous blood was taken from patients and from their family members (father and mother) in ethylenediaminetetraacetic acid-anticoagulated vacutainer for the purpose of the study. Genomic DNA was extracted from peripheral blood lymphocytes by phenol chloroform extraction method. Primers for MTHFR gene were designed. The polymerase chain reaction was carried out. After successful amplification, a small aliquot (5 μl) of the MTHFR reaction mixture was treated with 1 units of Hinf I restriction enzyme (NEB). Results were obtained and compiled.

RESULTS:

A total of 30 patients/participants with craniosynostosis of Indian descent and their parents formed the study group. The genotyping did not confirm an association between the MTHFR 677C to T polymorphism and between different categories of craniosynostosis. When comparing the offspring of mothers statistically significant differences were found.

CONCLUSION:

C667T polymorphism of the MTHFR gene is unlikely to play a role in the pathogenesis of craniosynostosis though maternal MTHFR C677T polymorphism may be a genetic risk factor.     

Growth of cranial synchondroses and sutures requires polycystin-1

In vertebrates, coordinated embryonic and postnatal growth of the craniofacial bones and the skull base is essential during the expansion of the rostrum and the brain. Identification of molecules that regulate skull growth is important for understanding the nature of craniofacial defects and for development of non-invasive biologically based diagnostics and therapies.Here we report on spatially restricted growth defects at the skull base and in craniofacial sutures of mice deficient for polycystin-1 (Pkd1). Mutant animals reveal a premature closure of both presphenoid and sphenooccipital synchondroses at the cranial base. Furthermore, knockout mice lacking Pkd1 in neural crest cells are characterized by impaired postnatal growth at the osteogenic fronts in craniofacial sutures that are subjected to tensile forces. Our data suggest that polycystin-1 is required for proliferation of subpopulations of cranial osteochondroprogenitor cells of both mesodermal and neural crest origin during skull growth. However, the Erk1/2 signalling pathway is up-regulated in the Pkd1-deficient skeletal tissue, similarly to that previously reported for polycystic kidney.     

Early onset of craniosynostosis in an Apert mouse model reveals critical features of this pathology

Activating mutations of FGFRs1-3 cause craniosynostosis (CS), the premature fusion of cranial bones, in man and mouse. The mechanisms by which such mutations lead to CS have been variously ascribed to increased osteoblast proliferation, differentiation, and apoptosis, but it is not always clear how these disturbances relate to the process of suture fusion. We have reassessed coronal suture fusion in an Apert Fgfr2 (S252W) mouse model. We find that the critical event of CS is the early loss of basal sutural mesenchyme as the osteogenic fronts, expressing activated Fgfr2, unite to form a contiguous skeletogenic membrane. A mild increase in osteoprogenitor proliferation precedes but does not accompany this event, and apoptosis is insignificant. On the other hand, the more apical coronal suture initially forms appropriately but then undergoes fusion, albeit at a slower rate, accompanied by a significant decrease in osteoprogenitor proliferation, and increased osteoblast maturation. Apoptosis now accompanies fusion, but is restricted to bone fronts in contact with one another. We correlated these in vivo observations with the intrinsic effects of the activated Fgfr2 S252W mutation in primary osteoblasts in culture, which show an increased capacity for both proliferation and differentiation. Our studies suggest that the major determinant of Fgfr2-induced craniosynostosis is the failure to respond to signals that would halt the recruitment or the advancement of osteoprogenitor cells at the sites where sutures should normally form.     

Jagged1 functions downstream of Twist1 in the specification of the coronal suture and the formation of a boundary between osteogenic and non-osteogenic cells

The Notch pathway is crucial for a wide variety of developmental processes including the formation of tissue boundaries. That it may function in calvarial suture development and figure in the pathophysiology of craniosynostosis was suggested by the demonstration that heterozygous loss of function of JAGGED1 in humans can cause Alagille syndrome, which has craniosynostosis as a feature. We used conditional gene targeting to examine the role of Jagged1 in the development of the skull vault. We demonstrate that Jagged1 is expressed in a layer of mesoderm-derived sutural cells that lie along the osteogenic-non-osteogenic boundary. We show that inactivation of Jagged1 in the mesodermal compartment of the coronal suture, but not in the neural crest compartment, results in craniosynostosis. Mesodermal inactivation of Jagged1 also results in changes in the identity of sutural cells prior to overt osteogenic differentiation, as well as defects in the boundary between osteogenic and non-osteogenic compartments at the coronal suture. These changes, surprisingly, are associated with increased expression of Notch2 and the Notch effector, Hes1, in the sutural mesenchyme. They are also associated with an increase in nuclear β-catenin. In Twist1 mutants, Jagged1 expression in the suture is reduced substantially, suggesting an epistatic relationship between Twist1 and Jagged1. Consistent with such a relationship, Twist1-Jagged1 double heterozygotes exhibit a substantial increase in the severity of craniosynostosis over individual heterozygotes. Our results thus suggest that Jagged1 is an effector of Twist1 in coronal suture development.     

Multiple joint and skeletal patterning defects caused by single and double mutations in the mouse Gdf6 and Gdf5 genes

Growth/differentiation factors 5, 6, and 7 (GDF5/6/7) represent a distinct subgroup within the bone morphogenetic protein (BMP) family of secreted signaling molecules. Previous studies have shown that the Gdf5 gene is expressed in transverse stripes across developing skeletal elements and is one of the earliest known markers of joint formation during embryonic development. Although null mutations in this gene disrupt formation of some bones and joints in the skeleton, many sites are unaffected. Here, we show that the closely related family members Gdf6 and Gdf7 are expressed in different subsets of developing joints. Inactivation of the Gdf6 gene causes defects in joint, ligament, and cartilage formation at sites distinct from those seen in Gdf5 mutants, including the wrist and ankle, the middle ear, and the coronal suture between bones in the skull. Mice lacking both Gdf5 and Gdf6 show additional defects, including severe reduction or loss of some skeletal elements in the limb, additional fusions between skeletal structures, scoliosis, and altered cartilage in the intervertebral joints of the spinal column. These results show that members of the GDF5/6/7 subgroup are required for normal formation of bones and joints in the limbs, skull, and axial skeleton. The diverse effects on joint development and the different types of joints affected in the mutants suggest that members of the GDF family play a key role in establishing boundaries between many different skeletal elements during normal development. Some of the skeletal defects seen in single or double mutant mice resemble defects seen in human skeletal diseases, which suggests that these genes may be candidates that underlie some forms of carpal/tarsal coalition, conductive deafness, scoliosis, and craniosynostosis.